Researchers hope to learn how a fruit fly thinks by accompanying it on a stroll.

Imagine a day in the life of the common fruit fly. He wakes up after a few hours of sleep. Using light and smell to guide his movements, he zips around at 30 centimeters per second in search of decaying fruit, dodging obstacles along the way. If he runs into a lady friend, he quivers his wings and sings her a sweet serenade.

A simple life, perhaps, and yet extraordinary: Drosophila melanogaster carries out this daily choreography using a brain that’s less than a millimeter across and holds just 100,000 neurons—a tiny fraction of the 75 million in a mouse or 100 billion in a human.

Vivek Jayaraman wants to capture, in real time, how the fly’s brain responds to a changing environment. Ultimately, he hopes to uncover very basic patterns—“algorithms”—of fly brain activity that hold true in more complex brains including, presumably, ours.

As a first step toward that goal, Vivek’s team has designed a technique that monitors the activity of specific sets of neurons while a fly is walking. The experimental setup can be adapted to study flying behavior as well, the researchers say.

“Think of this preparation as a kind of virtual reality for the fly,” says Vivek, a group leader at HHMI’s Janelia Farm Research Campus. “You tightly control the sensory environment but allow the fly to control its own movements. By adjusting parameters in this world, you can get some sense of how the brain translates perception into action.”

		Inside the Brain of a Fly on the Move See what it takes to assemble a window into a fly’s brain.

But designing such virtual worlds is no easy feat. The most commonly used technique for measuring fly brain activity—calcium imaging—typically doesn’t allow the insects to be in a natural position, let alone move freely. In this kind of imaging, insects are genetically engineered so that certain sets of neurons carry calcium-sensitive proteins that glow green when activated. Specially designed microscopes can then pick up the light signals when those neurons are active, allowing scientists to study basic neural function in the flies.

For the past three years, Vivek and postdoctoral fellows Johannes Seelig and Eugenia Chiappe have been revamping their recording setup so that it can be used while a fly is walking.

With their technique, published in the July 2010 issue of Nature Methods, the fly is temporarily knocked out so that the skin on its head can be removed, exposing the brain. Researchers glue the neck and thorax of the insect to a chamber mounted on a two-photon microscope. The fly’s legs are left to walk freely atop a tiny foam ball that’s floating on a column of air.

The tethered fly watches visual stimuli on a special display designed by Janelia Farm fellow Michael Reiser. An optical tracker measures the fly’s precise leg movements and correlates them with the brain activity picked up by the microscope or an electrode.

In nature, of course, the fly does not find itself bound in these sorts of restraints. “This is a compromised solution,” Vivek admits. But he hopes that many interesting behaviors, such as those involving walking responses to visual input, are not so different in a tethered insect. In 5 to 10 years, he predicts, researchers will have figured out how to record from a fly while it’s walking freely across an open space. In the meantime, the tethered preparation will do just fine.

Fruit flies make ideal experimental subjects because researchers can easily tinker with their genes. Thanks to thousands of fly lines engineered over the years—many developed recently by Janelia Farm director Gerry Rubin—scientists can obtain flies that carry genetic tags in just about any type of brain cell.

“That’s the very attractive thing about working with Drosophila—you can get some type of fly, and it will always have the same cells labeled,” notes Seelig. “That’s very different from most other species, where you have to somewhat randomly pick a cell to record from.”

Illustration: Ping Zhu

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